Although recent advances in the treatment and monitoring of HIV-1 infection have substantially diminished HIV-associated illness and mortality, the management of HIV-infected patients has become increasingly complex. Both the acute and long-term toxicities of the common antiretroviral medications are becoming better understood and continue to complicate the successful management of this condition. Alternative treatment strategies are clearly needed, both for patients with access to HAART and, on a worldwide basis, particularly for the much greater number of patients with little or no access to these expensive therapies. Our clinical research continues to address several important aspects of the following questions: how to optimally dose anti-retroviral drugs; how to integrate immune based therapies within a framework of antiretroviral therapy; how to develop a successful antiretroviral strategy that employs periodic interruptions of treatment in order to spare drug and/or reduce toxicities, and what happens to viral load and other measures after the discontinuation of successful anti-retroviral therapy. Studies employing interruptions of HAART on a daily, weekly, or monthly basis are ongoing and, in some cases, appear to indicate that periodic intervals of treatment interruption may offer therapeutic equivalence to continuous therapy. In addition, we continue our efforts to improve access to clinical trials by local minority populations through an outreach that includes a close relationship with local clinics for the medically under-served. In patients who had undetectable levels of plasma viremia during combination antiretroviral therapy for more than 1 year, we previously demonstrated that discontinuation of antiviral therapy promptly results in substantial viral relapse. Within two months of treatment cessation lymph node histology begins to revert to a state similar to primary infection in some cases.The kinetics of viral relapse appear unrelated either to the pre-cessation level of infection within the resting, latently-infected CD4 cell pool or to prior therapy with interleukin-2 when given in an effort to help lower viral levels within this pool. Independent lines of evidence now confirm that the rate of peripheral lymphocyte turnover accelerates markedly upon withdrawal of antiretroviral therapy and returns to baseline levels shortly after re-introduction of HAART, strongly suggesting that viral activity directly influences the rate of CD4 proliferation. Virologic rebound is associated with a profound decrease in antigen responsiveness within the CD4 pool that recovers upon restoration of viral suppression. Another major focus of this project has been to characterize the immunologic abnormalities associated with HIV infection, develop immunologic approaches to the therapy of patients with HIV infection, and utilize these immune based therapies as tools for obtaining additional insights into the pathophysiologic mechanisms present in patients with HIV infection. Specifically, this project is aimed at reversing the CD4 cell decline associated with progressive HIV-1 infection through the use of subcutaneous administration of interleukin-2. A series of randomized phase I-II studies were carried out that established this as a feasible method for increasing the CD4 count in patients with HIV infection; these studies were then extended to optimize the dosing regimens for maximal immunologic and virologic benefit while minimizing side effects. Intensive efforts are underway to better characterize the function, replication, and survival of lymphocytes following both acute and chronic stimulation by IL-2 therapy. Cohorts of patients are being followed who have received IL-2 treatment for periods that now extend beyond 8 years. Following completion of four separate Vanguard trials of subcutaneous IL-2 in Argentina, Thailand, Houston, and the United Kingdom in order to extend these observations to other populations, the laboratory has engaged in an extensive series of collaborations with a large number of extramural colleagues, both in the US and abroad, in the context of two major randomized phase III international clinical endpoint trials. The goal of these studies is to determine whether the favorable effects of IL-2 therapy on CD4 cell number translate into a significant delay in the onset of AID-defining conditions and/or death in recipients of IL-2 plus antiretrovirals versus patients on antiretoviral therapy alone. Interleukin-2 (IL-2) is also being studied for its potential role in supplementing HAART therapy, specifically to determine whether it can be used as a HAART-sparing regimen for those who experience an initial CD4 cell increase from its use. We have initiated a randomized, controlled trial of scIL-2 with and without HAART interruption in an effort to determine how successful IL-2 therapy will be in eliminating the need for continuous HAART. We are also actively engaged in the design and implementation of similar exploratory studies of HAART-sparing strategies with extramural collaborators to address different facets of this issue.